Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis
Yun He, Yan Luo, Shibo Tang, Iiro Rajantie, Petri Salven, Matthias Heil, Rong Zhang, Dianhong Luo, Xianghong Li, Hongbo Chi, Jun Yu, Peter Carmeliet, Wolfgang Schaper, Albert J. Sinusas, William C. Sessa, Kari Alitalo, Wang Min
Yun He, Yan Luo, Shibo Tang, Iiro Rajantie, Petri Salven, Matthias Heil, Rong Zhang, Dianhong Luo, Xianghong Li, Hongbo Chi, Jun Yu, Peter Carmeliet, Wolfgang Schaper, Albert J. Sinusas, William C. Sessa, Kari Alitalo, Wang Min
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Research Article Angiogenesis

Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis

Abstract

Bmx/Etk non-receptor tyrosine protein kinase has been implicated in endothelial cell migration and tube formation in vitro. However, the role of Bmx in vivo is not known. Bmx is highly induced in the vasculature of ischemic hind limbs. We used both mice with a genetic deletion of Bmx (Bmx-KO mice) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg mice) to study the role of Bmx in ischemia-mediated arteriogenesis/angiogenesis. In response to ischemia, Bmx-KO mice had markedly reduced, whereas Bmx-SK-Tg mice had enhanced, clinical recovery, limb perfusion, and ischemic reserve capacity when compared with nontransgenic control mice. The functional outcomes in these mice were correlated with ischemia-initiated arteriogenesis, capillary formation, and vessel maturation as well as Bmx-dependent expression/activation of TNF receptor 2– and VEGFR2-mediated (TNFR2/VEGFR2-mediated) angiogenic signaling in both hind limb and bone marrow. More importantly, results of bone marrow transplantation studies showed that Bmx in bone marrow–derived cells plays a critical role in the early phase of ischemic tissue remodeling. Our study provides the first demonstration to our knowledge that Bmx in endothelium and bone marrow plays a critical role in arteriogenesis/angiogenesis in vivo and suggests that Bmx may be a novel target for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease.

Authors

Yun He, Yan Luo, Shibo Tang, Iiro Rajantie, Petri Salven, Matthias Heil, Rong Zhang, Dianhong Luo, Xianghong Li, Hongbo Chi, Jun Yu, Peter Carmeliet, Wolfgang Schaper, Albert J. Sinusas, William C. Sessa, Kari Alitalo, Wang Min

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Figure 3

Critical roles of Bmx in the recovery of hind limb perfusion after injury.

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Critical roles of Bmx in the recovery of hind limb perfusion after injur...
(A) Hind limb ischemia was induced. Blood flow of ischemic (left) and nonischemic (right) limb were measured on gastrocnemius muscle at 30 minutes, 3 days, 2 weeks, and 4 weeks after surgery using the PeriFlux system with a Laser Doppler Perfusion module unit (LDPU). Tissues were harvested on day 28 for immunohistochemistry. In Bmx-KO mice, clinical score indicated a severe phenotype (B), leading to necrosis of limb (C). In contrast, Bmx-SK-Tg mice, like C57BL/6 mice, recovered completely after 4 weeks. (D) Bmx-SK-Tg mice showed augmented, whereas Bmx-KO mice showed reduced, recovery of limb perfusion compared with normal C57BL/6 mice (ratios of perfusion in nonischemic [left] limb to that in ischemic [right] limb are shown). (E and F) Bmx-SK-Tg mice show enhanced, while Bmx-KO mice show abnormal, postcontraction hyperemia. Adductor muscle groups of mice from before surgery (E) and 2 weeks after surgery (F) were electrostimulated, and increase in gastrocnemius blood flow was recorded. Both baseline and stimulated lower leg perfusion were measured as an index of the maximal vasodilatory capacity. Data are mean ± SEM; *P < 0.05. stim, stimulation.